neurotoxicity and mechanisms of induced hyperexcitability

INTRODUCTIONSchizophrenia is a chronic and severe psychiatric disorderthat generally occurs in late adolescence or earlyadulthood. Approximately 1% of the population worldwideis affected by schizophrenia, placing a heavy burdenon society, both in terms of emotional suffering and economicloss [1]. Schizophrenia is the classic example of adisorder that always has psychosis as one of its features[2]. As psychotic episodes are extremely debilitating,management and treatment aim to reduce and eliminatethese dramatic personality changes, consisting of irritability,confusion and paranoia associated with hallucinationsand delusions. Antipsychotic drugs are used to treatnearly all forms of psychosis, including schizophrenia.It has been generally accepted that the mechanism bywhich antipsychotic drugs decrease hallucinations anddelusions is mediated at least in part by dopamine D 2receptorblockade [3-5]. Moreover, atypical antipsychoticdrugs, such as olanzapine, display a unique neuropharmacologicalprofile; they minimise psychoses by interactingwith a number of neurotransmitter and receptorsystems through binding at multiple receptor sites. Olanzapinehas a high affinity for serotonin 5 HT 2A, dopamine,cholinergic, histamine and α1-adrenergic receptors [6].However, the most important mechanisms underlyingthe clinical properties of atypical antipsychotic drugs appearto be mediated by interactions with the serotonin5-HT 2Areceptor subtype [7, 8].Serotonin is one of the major neurotransmitters in thehuman brain and plays a central role in the regulation ofa wide range of behaviours, such as mood, eating and thestress response [9-11]. The serotonergic projections arisingfrom the brainstem raphe nuclei form the largest andmost complex efferent system in the human brain [12, 13].The axons of dorsal raphe nucleus (DRN) neurons contributeto the majority of the serotonergic innervation in thefrontal cortex, ventral hippocampus and striatal regions[14, 15], while the axons of median raphe nucleus (MRN)serotonergic neurons are more abundant in the dorsal hippocampusand the cingulate cortex [16, 17]. The hypothalamus,the substantia nigra and the nucleus accumbensreceive serotonergic innervation from both nuclei [18, 19].This organisation of the serotonergic neuronal populationsuggests that serotonin is involved in the regulation of differentfunctional systems, such as the motor, limbic andsomatosensory systems [13]. Thus, it is not surprising thatatypical antipsychotic medications target multiple brainserotonin receptor subtypes. As it is very difficult to assessalterations of serotonergic transmission in the pathophysiologyof psychiatric disorders in the living human brain,animal models are needed.Animal models of psychiatric disorders, includingschizophrenia, rely on mimicking specific aspects orsymptoms associated with the disease [20-22]. The twomost widely used models are locomotor hyperactivity inducedby psychotomimetic drugs and prepulse inhibition.Psychotomimetic drugs, such as amphetamine and phencyclidine,can induce abnormal behaviours in animals andmimic certain aspects of psychotic disorders in humans[20, 23-25]. Amphetamine, an indirectly acting sympathomimetic,causes increased dopamine release from presynapticterminals [26], and hyperlocomotion induced byamphetamine is dependent upon intact subcortical dopamineactivity in the nucleus accumbens [27]. In contrast,phencyclidine interferes with multiple neurotransmittersystems [28]. Phencyclidine acts as a non-competitiveantagonist at the ion channel associated with the N-methyl-D-aspartate (NMDA) glutamate receptor andalso indirectly facilitates dopaminergic and serotonergictransmission [29]. Similar mechanisms are also activatedin humans by phencyclidine [30]. Prepulse inhibition ofthe acoustic startle response is an operational measureof sensorimotor gating that is disrupted in patients withschizophrenia [31, 32] and in rats treated with drugs thatfacilitate dopaminergic activity [33-35]. Furthermore,prepulse inhibition is reduced in rats treated systemicallywith serotonin releasers, such as fenfluramine, direct 5HT 1Areceptor agonists [36-38] and glutamate receptorantagonists, such as phencyclidine [39]. The prepulseinhibition-acoustic startle reflex model in rats offers aunique opportunity to asses attentional and informationprocessing deficits in schizophrenia, as modulation of thestartle responses is similar among mammalian species[40]. In animals, usually the whole body startle responseis measured after exposure to acoustic or tactile stimuli,while in humans the eyeblink component of the startleresponse is measured [40].There is a growing body of evidence that suggests thatthe hippocampus, amygdala and prefrontal cortex play animportant role in the pathogenesis of schizophrenia. The activityof these brain regions may cause changes in subcorticaldopaminergic activity and therefore lead to the inappropriateinitiation of behavioural responses to external stimuli.We have previously reported that serotonergic projectionsinto the hippocampus and amygdala are differentially involvedin the regulation of psychotomimetic drug-inducedlocomotor hyperactivity and prepulse inhibition [41, 42]. Asserotonergic projections from both raphe nuclei innervatethe prefrontal cortex, in addition to the hippocampus andamygdala, the aim of the present study was to determinewhether serotonergic lesions of the prefrontal cortex causedbehavioural changes similar to those produced by lesions ofthe hippocampus and/or amygdala.In humans, dysfunction of the prefrontal cortical areas,with which the medial prefrontal cortex of the ratis comparable, is related to psychopathology of schizophreniaand other psychiatric disorders (for a review,see [43]). A wealth of evidence from studies in animalsand humans indicates that the medial prefrontal cortex(mPFC) is a key component of the cortico-limbic-striatalcircuits that generate pathological emotional behaviour[44, 45]. The various subdivisions of the mPFC appear toserve separate and distinct functions. For example, ven-12